Project Abstract Bioequivalence studies that compare a reference formulation to an investigational generic formulation typically are conducted in healthy adult volunteers and occasionally are conducted in patients. Some populations have unique physical, biological, and physiological considerations that are not reflected by healthy volunteers or by the typical patient for whom a drug is indicated. Mixed evidence of the appropriateness of generic substitution and adverse events associated with generic substitution calls attention to the safety and efficacy profiles of generic drugs. Furthermore, there is a paucity of evidence in barriers to and patterns of generic substitution in special populations whose experiences with a drug are not represented by those in whom bioequivalence studies are conducted. The purpose of the proposed research is to identify research needs, monitor, and improve generic drug substitution in special populations. We propose to use a mixed-methods approach including systematic review of the literature, key informant interviews, focus groups, and secondary data analysis of Medicare and Medicaid claims data to fully explore the practice patterns of generic drug utilization and substitution in special populations. To achieve this, we propose the following three specific aims: 1) to collect information on practice patterns in special populations to assess possible barriers to generic substitution; 2) to compare clinical practice with labeled drug administration information in selected special populations to identify factors that raise issues for safety and effectiveness with generic substitution; and 3) to analyze generic drug utilization and substitution patterns and identify the impact of product-level, patient-level, and provider-level factors on generic drug substitution among special populations. The six special populations that we will focus on include pediatric patients, women, older adults with multiple medications, racial/ethnic minorities, individuals with impaired kidney or liver function, and individuals residing in different geographic regions or settings. We will conduct a systematic review to understand the evidence documenting differences in generic substitution patterns among special populations. We will evaluate the relevance of product labeling and drug reference resources to special populations. Qualitative key informant interviews and focus groups will contribute to development of profiles of barriers for generic substitution among special populations. Quantitative data analysis of relevant subgroups will allow comparisons of population-level generic drug utilization and substitution patterns, as well as identify factors associated with generic drug substitution. The expected outcomes of this study are provision of information to identify research needs and strategies to improve monitoring of generic drug substitution in special populations, which can help to overcome barriers to generic drug use in the U.S.